Antigen Recognition by Variable Lymphocyte Receptors (VLR) in the Sea Lamprey

海七鳃鳗可变淋巴细胞受体 (VLR) 的抗原识别

• 批准号: 0614672
• 负责人: Zeev Pancer
• 金额: --
• 依托单位: University of Maryland Biotechnology Institute
• 依托单位国家: 美国
• 项目类别: Continuing grant
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0614672&HistoricalAwards=false
• 关键词: Antigen; Recognition; Variable; Lymphocyte; Receptors

Two types of recombinatorial adaptive immune systems appeared at the dawn of vertebrate radiation ~500 million years ago. Jawed vertebrates generate a diverse repertoire of B and T cell antigen receptors through V(D)J rearrangement of immunoglobulin (Ig) gene fragments. In sharp contrast, jawless vertebrates such as the sea lamprey, assemble their variable lymphocyte receptors (VLR) through recombinatorial insertion of diverse leucine-rich repeat (LRR) modular units, from flanking cassettes into the germline VLR gene. The combinatorial diversity of the repertoire is about 1014 unique antigen receptors, both for the LRR and the Ig-based adaptive immune systems. This is intriguing when considering that jawless and jawed vertebrates are the only two vertebrate taxons that survived from the Cambrian period. What was the selective pressure to evolve not one but two different types of rearranging lymphocyte antigen receptors? Did VLRs and antibodies evolve by chance and necessity to recognize similar, or perhaps different determinants of the antigenic world? The role of VLRs in lamprey immunity will be explored in this project. Antigen recognition by VLR will be studied in animals immunostimulated with various types of antigens, including foreign proteins, microbial cell wall components, and microbial DNA and RNA. Libraries of VLRs will be constructed from lymphocytes of immunized animals, to select those receptors that can bind the antigens with high specificity. Selected VLRs bound to their cognate ligand will then be crystallized, to determine the three-dimensional structure of the complexes, and to identify contact residues between the VLR and its ligand. Functional and structural characterization of the VLR may help elucidate the origin of adaptive immunity, in particular since LRR modules are also the building blocks of our own cardinal innate microbial detection receptors, such as the Toll-like receptors and the cytoplasmic NBS-LRR family members, and the LRR-containing Disease Resistance genes of plants. This project will involve the training of several students at varying academic backgrounds. In addition, Dr. Pancer will incorporate his research results in teaching a course in comparative and evolutionary immunobiology.

两种类型的重组适应性免疫系统出现在约5亿年前脊椎动物辐射的黎明。有颌脊椎动物通过免疫球蛋白（IG）基因片段的V（D）J重排产生多种多样的B和T细胞抗原受体。与此形成鲜明对比的是，无颌脊椎动物，如海七鳃鳗，组装其可变淋巴细胞受体（VLR），通过重组插入不同的富含亮氨酸的重复序列（LRR）模块化单位，从侧翼盒到种系VLR基因。库的组合多样性是约1014个独特的抗原受体，用于LRR和基于Ig的适应性免疫系统。考虑到无颌和有颌脊椎动物是寒武纪时期幸存下来的仅有的两种脊椎动物分类群，这是有趣的。进化出两种不同类型的淋巴细胞抗原受体的选择压力是什么？VLRs和抗体的进化是否出于偶然和必要，以识别抗原世界中相似或不同的决定簇？本计画将探讨VLRs在七鳃鳗免疫中的角色。将在用各种类型的抗原（包括外源蛋白、微生物细胞壁组分以及微生物DNA和RNA）免疫刺激的动物中研究VLR的抗原识别。将从免疫动物的淋巴细胞构建VLR文库，以选择能够以高特异性结合抗原的那些受体。然后将与其同源配体结合的所选VLR结晶，以确定复合物的三维结构，并鉴定VLR与其配体之间的接触残基。VLR的功能和结构表征可能有助于阐明适应性免疫的起源，特别是因为LRR模块也是我们自己的主要先天微生物检测受体的构建块，例如Toll样受体和细胞质NBS-LRR家族成员，以及植物的含LRR的抗病基因。该项目将涉及对不同学术背景的几名学生进行培训。此外，Pancer博士将把他的研究成果纳入比较和进化免疫生物学课程的教学中。